Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols

ABSTRACT

This invention relates to the composition of a biologically compatible high concentration solution of progesterone, which is stable and non-toxic, and which can be used transdermally, orally, and in suppository and pessary form for the correction of progesterone deficiency states and other diseases.

The present invention relates to the composition of a biologicallycompatible high concentration solution of progesterone in tocopherol,with or without modifying substances, which can be used transdermally,orally, and in suppository and pessary form, for the correction ofprogesterone deficiency states and other diseases.

Progesterone deficiency can be defined in relation to a norm, and alsoin relative terms, taking into account the absolute level ofprogesterone in the tissues and the presence and levels of antagoniststo its actions, including estrogens, prolactin, and androgenic steroids,and it can also be defined in the empirical sense, in which symptomsabate when progesterone is administered.

Physicians have long sought an oral and/or transdermal form ofprogesterone which is stable in high concentration and which isassimilated easily by the body, for use when injectable forms ofprogesterone are not tolerated. A non-toxic and low-allergenic form isof special value for use in allergic patients, and for all users theabsence of a toxic solvent is of obvious value.

Many physicians have used progesterone dissolved in ethanol, but ethanolhas a higher mutual solubility with water than with progesterone,causing the bulk of the progesterone to be crystallized out of solutionas the alcohol solvent mixes with biological fluids. That composition isineffective because it fails to deliver progesterone in practicalquantities and usable form. Other compositions containing solvents suchas benzyl benzoate, benzoyl alcohol or phenol are limited in theirapplicability because of their toxicity, irritating properties, orallergenicity. Since allergies are common in the condition ofprogesterone deficiency, it follows that the effectiveness ofcompositions containing allergenic solvents is limited.

Progesterone has been used medically to treat pregnancy complications,menstrual abnormalities, menopausal difficulties, several types ofmalignant and non-malignant tumors, neurological and psychologicalsymptoms, and many other specific problems. The composition described inthis patent can be used effectively for all of the purposes for whichprogesterone in its older compositions is effective. In addition, thecomposition described in this patent is useful for several new purposes,including treatment of psoriasis, eczema, senile skin changes includingwarts, superficial burns, allergies, abnormal hair growth resulting fromandrogen excess, intestinal inflammation and bowel spasms, migraine, andfor promoting maturation of thymus-derived lymphocytes, and as acontraceptive.

It is an object of the present invention to provide a composition andmethod for the treatment of progesterone deficiency conditions.

It is another object of the present invention to provide such acomposition and method which overcome the shortcomings of the prior art.

It is another object of the present invention to provide a compositionwhich does not decompose into solvent and crystallized solute,progesterone, under any presently known conditions of storage or use.

It is another object of the present invention to provide such acomposition which is non-toxic and which may be used frequently overlong periods without adversely affecting the tissues which it contacts.

It is a further object of the present invention to provide such acomposition which is economical and easily used for the prevention andtreatment of progesterone deficiency conditions and other diseases.

Still further objects and the entire scope of applicability of thepresent invention will become apparent from the detailed description andspecific examples, but it should be understood that the examples, whileindicating preferred embodiments of the invention, are given only forillustration, since changes within the spirit and scope of the inventionwill become apparent to those skilled in the art from this description.

It has been found that the above objects may be attained by acomposition which contains as essential ingredients progesterone andtocopherol. As will be hereinafter explained more fully, the compositionmay also contain additives for various purposes. The composition may beadministered by spreading on the skin, by holding in contact with mucousmembranes, or by ingesting, and can be used as frequently as needed.

Suitable forms of tocopherol include d-alpha tocopherol, and mixedtocopherols of the dextro-rotatory form.

Suitable additives include coconut oil, palm kernel oil, jojoba oil, andolive lil, used in concentrations up to about 15% to lower the viscosityof the solution and to thus speed absorption; ascorbyl palmitate and/orglyceryl monophosphate in concentrations sufficient to emulsify thecomposition with water; biological or organic gels including aloe geland extracts from marine algae to thicken the consistency and tostabilize the emulsion; and ethanol, in a concentration of up to about7% by volume, to modify consistency and to increase absorption ofprogesterone.

The composition is prepared by mixing the ingredients to obtain ahomogeneous product. Stirring at room temperature is adequate, but mayrequire several days to reach complete homogeneity. An oxygen-freeatmosphere is preferred but not essential. If higher temperatures areused for faster mixing, an oxygen-free atmosphere becomes more importantto prevent oxidation of the materials.

Progesterone and tocopherol can be mixed in the proportions of from 1%to about 25% progesterone by weight, to about 75% to 99% of tocopherol,with a preferred concentration for most uses of from about 10% to 20%progesterone to about 80% to 90% tocopherol.

This invention is further described in the following specific examples,which are to be considered only as illustrative of preferred embodimentsof the present invention.

EXAMPLE 1

Ten kilograms of progesterone is added to 90 kilograms of mixedtocopherols of the dextro-rotatory form, and stirred at a temperature of45° C. until homogeneous. Thirty-five kilograms of glyceryl-monostearateis added to the composition and stirred at 45° C. until a homogeneousmixture is produced. This oil phase is then homogenized at 45° C. with awater phase composed of 200 kilograms of water mixed homogeneously with5 kilograms of dry aloe gel, and one kilogram of sorbic acid as apreservative.

The resulting emulsion is then applied to the skin in treating systemicprogesterone deficiency, and for treating local skin conditionsincluding psoriasis, or applied to a vaginal diaphragm or pessary orinserted vaginally with an appropriate applicator, for use as acontraceptive or for treating systemic progesterone deficiency.

EXAMPLE 2

Twenty kilograms of progesterone is added to 80 kilograms of mixedtocopherols, and stirred at a temperature of 40° C. until homogeneous.

The resulting composition is applied to a pessary for use as acontraceptive, or as a local treatment for dysplasia of the uterinecervix, or is administered orally for treatment of a systemicprogesterone deficiency. No preservative is needed in this composition.

EXAMPLE 3

Ten kilograms of progesterone is added to 90 kilograms of d-alphatocopherol and stirred at a temperature of 30° C. until homogeneous.

The resulting composition is then encapsulated and administered orallyfor treatment of systemic progesterone deficiency.

What is claimed is:
 1. A composition consisting essentially ofprogesterone solubilized in tocopherol.
 2. A pharmaceutical compositionsuitable for administering progesterone to a patient in need thereof,comprising a pharmaceutically effective amount of progesteronesolubilized in tocopherol.
 3. The composition of claim 2 whereinprogesterone is present at a concentration of from about 1% to about 25%by weight.
 4. The composition of claim 2 also containing an emulsifier,water and a preservative.
 5. A method for administering progesterone toa patient in need thereof comprising administering to said patient bymeans other than intravenous injection, a pharmaceutically effectivemixture of progesterone solubilized in tocopherol.
 6. The method ofclaim 5 which comprises the oral administration of said mixture.
 7. Themethod of claim 5 which comprises the topical administration of saidmixture.
 8. The method of claim 5 which comprises placing said mixturein contact with the mucous membranes of the patient.
 9. The method ofcontraception in which a pharmaceutically effective amount ofprogesterone solubilized in tocopherol is applied to the vaginalmembranes and the uterine cervix by means of a vaginal diaphragm, apessary, or other means of vaginal application in which the compositionis retained within the vagina for about four hours or more after eachapplication.
 10. A method for making a pharmaceutically effectivecomposition for the administration of progesterone to a patient in needthereof comprising solubilizing progesterone in tocopherol.